Mycobacterium tuberculosis (M. tuberculosis) is an intracellular bacteria capable of evading the human immune system through various mechanisms. M. tuberculosis secretes many virulence factors when infecting host cells. The 6 kDa early secretory antigen target (ESAT-6) is one of the most virulent factors producted by the ESX-1 system, which acts alone or in conjunction with culture filtrate protein 10 (CFP-10) to involve in host-pathogen interactions. ESAT-6 has been widely investigated in M. tuberculosis pathogenicity and vaccination. Nonetheless, little is known about its contribution to M. tuberculosis immune evasion and the involved cellular mechanisms. In this study, differential genes between BCG with the region of difference-1 (RD1) gene and Bacille Calmette-Guérin (BCG) infected dendritic cells (DC) were analyzed to reveal that ESAT-6, expressed in the RD1 region, involves host denfensive function of DC in response to BCG. In vitro evidence indicated that ESAT-6 (5 μg/ml) inhibits M. tuberculosis-induced apoptosis in THP-1(A) macrophages by suppressing TLR2 and via caspase-9 and caspase-3 endogenous pathways. It also inhibits the expression of IL-10, TNF-α, IL-12, and the phagocytosis of macrophages. Additionally, ESAT-6 suppresses the bactericidal activity of macrophages, including ROS production, and the killing of M. tuberculosis. In summary, these data suggest a central role of ESAT-6 in M. tuberculosis’s evasion from macrophage recognition, phagocytosis, killing, and apoptosis. Our work may provide a theoretical basis for exploring new molecular targets of M. tuberculosis both for innovative vaccines and therapeutic inventions.